Novel 21,21-dichlorosteroids

ABSTRACT

21,21-Dichlorosteroids of the formula   WHEREIN R1 is a hydrogen or chlorine atom; R2 is a hydrogen atom, a fluorine atom, or a methyl group; R3 is a hydrogen atom or a methyl group; R4 is a hydrogen atom or a free or esterified hydroxy group; and C1-C2 represents a single or double bond joining the carbon atoms at the 1- and 2-positions, have antiinflammatory activity.

United States Patent Laurent et al.

[ 51 Aug. 1, 1972 [54] NOVEL 21,21-DICHLOROSTEROIDS [72] Inventors: Henry Laurent; Karl H. Kolb; Rudolf Wiechert, all of Berlin, Germany [73] Assignee: Schering Aktiengesellschaft, Berlin,

Germany [22] Filed: July 22, 1970 211 App1.No.: 57,334

[30] Foreign Application Priority Data Primary Examiner-Henry A. French Attorney-Millen, Raptes & White [57] ABSTRACT 21,2l-Dichlorosteroids of the formula wherein R is a hydrogen or chlorine atom; R is a hydrogen atom, a fluorine atom, or a methyl group; R is a hydrogen atom or a methyl group; R. is a hydrogen atom or a free or esterified hydroxy group; and C -C represents a single or double bond joining the carbon atoms at the 1- and 2-positions, have antiinflammatory activity.

13 Claims, No Drawings BACKGROUND OF THE INVENTION fault wherein R is a hydrogen or chlorine atom; R is a hydrogen atom, a fluorine atom, or a methyl group; R is a hydrogen atom or a methyl group; R is a hydrogen atom or a free or esterified hydroxy group; and C,'-C represents a single or double bond joining the carbon atoms at the land 2-positions, having anti-inflammatory activity, are produced by reacting the corresponding A -2l-monochloro steroid with hydrogen fluoride in the presence of positive chlorine.

DETAILED DISCUSSION Examples of the compounds of this invention are those represented by Formula I wherein a. R is H, e.g., those wherein R is H or OH;

b. R is Cl, e.g., those wherein R is H or OH;

c. R is F, e.g., those wherein R is H or OH;

(I. C,C is a double bond, e.g., those wherein R is H or OH; and

e. each of a, b, c and d wherein R is CH When R is an esterified hydroxy group, the acyl group can be that of an acid which is customarily employed in steroid chemistry for the esterification of free hydroxy groups. Preferred acids are those containing up to 15 carbon atoms, especially lower and medium aliphatic carboxylic acids. Furthermore, the acids can also be unsaturated, branched, polybasic, or substituted in a conventional manner, for example by hydroxy or amino groups, or halogen atoms. Likewise suitable are cycloaliphatic, aromatic, mixed aromatic or heterocyclic acids which can also be substituted in a suitable manner.

Examples of such esters are those wherein R is -Ac in which Ac is the acyl radical of an organic carboxylic acid containing from 1 to 15 carbon atoms, inclusive, for example, a lower-aliphatic acid, e.g., formic, propionic, butyric, isobutyric valeric, iso-valeric, trimethylacetic, 2-methylbutyric, 2-ethylbutyric, hexanoic, diethylacetic, triethylacetic, heptanoic, octanoic,a ethylisovaleric, which can be optically active, e. g., abietic, an alicyclic acid, e.g., cyclopropylidene acetic, a cycloaliphatic acid, e.g., cyclopentylformic, cyclopentylacetic, B-cyclopentyl-propionic, cyclohexylformic, cyclohexylacetic, ficyclohexylpropionic, an aryl or alkaryl acid, e.g., benzoic, 2,3 or 4-methylbenzoic, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5- dimethyl- 2 benzoic, ethylbenzoic, 2,4,6-trimethylbenzoic, 2,4,6- triethylaceu'c, a-naphthoic, 3-methylu naphthoic, an aralkyl acid, e.g., phenylacetic, phenylpropionic,

diphenylacetic, triphenylacetic acid. Preferred are the esters of lower-aliphatic acids containing two to 12 carbon atoms. Also, esters of inorganic acids, such as, for example, of sulfuric and phosphoric acid, can be employed.

It will be apparent that the above-described compounds of this invention wherein R is OAc can be produced from the corresponding starting compound of Formula H wherein R also is OAc by the process of this invention or from corresponding compound of this invention of Formula I wherein R is OI-I by esterification techniques known in the art.

In carrying out the process of this invention, a compound of Formula I is produced by the reaction of a starting steroid of the formula CHzCl wherein R R R, and R and C,-C have the values given above,with hydrogen fluoride in the presence of positive chlorine.

The progression of the process according to the invention was surprising since it would not be expected that, under the conditions of this process, there would simultaneously occur the chlorine-fluorine addition to the M -double bond, and additionally chlorination at the 2l-position with resultant formation of the corresponding 2 l ,2 l dichloro-compounds.

In carrying out the process of this invention, the starting A "-2l-chloro steroid and selected N- chloroacylamide or imide in solid form or dissolved in an inert solvent, is mixed with the hydrogen fluoride.

Suitable inert solvents are liquid-saturated aliphatic and alicyclic and aromatic hydrocarbons, which can also be halogenated, such as, for example methylene chloride, ethylene dichloride, chloroform, hexane, octane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, or ether, e.g., tetrahydrofuran, dioxane, diethyl ether, and the like. Preferred solvents are the halogenated hydrocarbons, especially, methylene chloride or ethylene chloride, and the ethers, especially, tetrahydrofuran and dioxane, and dipolare aprotonic solvents, such as formamide, dialkylformamide, e.g. dimethyl formamide, dialkyl acetamide, e.g. dimethyl acetamide, N-methyl pyrrolid-2-one and acetonitrile.

The reaction is conducted at any convenient temperature, e.g. 20 C to room temperature or higher, preferably about 5 C to 0 C. Heating above room temperature is not usually desirable and some cooling usually is employed to maintain the reaction temperature at 15 C or lower, e.g. about 0 C.

The reaction is conducted until the chlorinationfluorination of the A -double bond and replacement of the hydrogen atom in position 21 of the starting steroid is substantially complete, e.g., several hours or longer at C., usually three or more hours.

The chlorine is supplied by a source of positive chlorine, e.g., N-chloroamides and N-chloroimides which preferable are derivatives of monoand dicarboxylic acids, respectively, containing up to carbon atoms. included are those of the formulae R- CONHCI, OCNC1OCR and (RCO) NCl wherein R is a monovalent and R is a divalent saturated or unsaturated hydrocarbon radical of less than 20 carbon atoms. Specific examples are the N-chloroderivatives of acylarnides', e.g., N-chloro-acetamide and N-chloro-imides, e.g., N-chloro-succinimide, phthalimide, and N-chloroarylamides, e. g., benzamide.

The amount of N-chloro compound employed is about 2 to 4, preferable about 3 moles calculated on one mole of the starting steroid. Especially suitable as the chlorination reactant are N-chlorosuccinimide and N-chloroacetamide.

In the process of this invention, the hydrogen fluoride is preferable substantially anhydrous. It preferably is employed in substantial molar excess to ensure complete reaction. Usually at least about 20 molar equivalents, calculated on the starting steroid, of hydrogen fluoride is employed. The concentration of the hydrogen fluoride in the reaction mixture is not critical and can vary widely.

In a preferred embodiment of the process of this invention, a hydrogen fluoride solution, for example in tetrahydrofuran/methylene chloride or dimethylformamide, is prepared at a low temperature, e.g. at 50C. The starting steroid (ll) and the chlorinating agent, for example N-chlorosuccinimide, are then added to this solution. The thus-produced reaction mixture is then allowed to stand for several hours, e.g., about 16-24 hours, at about 0C to 30C.

The order of mixing of the hydrogen fluoride with the starting steroid is not critical. The N-chloro compound should be present at the time of mixing to avoid the production of byproducts. Preferably the starting steroid and N-chloro compound are added to a solution of hydrogen fluoride in the reaction solvent.

The reaction product is worked up in the usual fashion, e.g., by mixing with ice water optionally containing sufficient base, e. g., ammonium hydroxide sodium carbonate or sodium bicarbonate, to neutralize the acid in the reaction mixture; separating the organic phase, removing the solvent and recrystallizing the product.

The starting 21-chloro compounds employed in the process of this invention can be prepared from the corresponding 21-hydroxy M -steroids by conventional procedures. For example the 2l-hydroxy-compound can be esterified with methanesulfonic acid chloride in pyridine at 0C. to produce the 2l-mesyloxy ester thereof and then substituting the mesyloxy group in the usual manner with a chlorine atom, preferably in dimethylformamide with lithium chloride (approximately 1 hour at 100C.) In Table l below are set forth physical data obtained for the thus-produced 2imesyloxy charging 2l-chloro and the intermediates starting 2 1 -hydroxy compounds of this process TABLE I Melting Point [0: in CHCLJ fix -Fluoro-2 1 -hydroxylfn -methyl-4,9( l l pregnadiene-3,20- dione fix -Fluoro-2 l-hydroxy- 16a -methyl- 1 ,4,9( l l pregnatriene-Il,20- dione 6a -Fluoro-2-chloro'2 1- hydroxyl 6: -methyll ,4,9( l l pregnatriene 3 ,20- dione l 7,2 l-Dihydroxyl ,4,9( l l pregnatriene-3 ,20 dione 61-Fluoro-2 l mesyloxy- 1 6 methyl-4,9( l l pregnadiene-3 ,20- dione 6 -Fluoro-2 lmesyloxy-l (n methyl-1,4301)- pregnatriene-3 ,20- dione 61 Flu0ro2chl0ro-2 lmesyloxy- 16 methyl-l ,4,9 l I pregnatriene-3 ,20- dione l7-Hydroxy-2 lmesyloxy-l ,4,9(1 pregnatriene-3,20- dione 61 -Fluoro-2 l-chlorol n -methyl-4,9( l I pregnadiene-3 ,20- dione (n -Fluoro-2 lchloro- 1 ,4,9( l 1 pregnatriene-3,20 dione (u -Fluoro-2,21-

dichloro- I Q methyl- 1 ,4,9( l l pregnatriene-3 ,20- dione 2 lChlorol 7-hydroxyl ,4,9( l l pregnatriene-3 ,20- dione I'M-175C +35 s l 6,800

229-230.5C +24 e =l 4 ,800

205-206 .5C +7 2 s =l 6 ,300

The novel compounds of this invention possess excellent topical anti-inflammatory activity. Such activity can be shown clinically by the skin blanching vasoconstriction test for topical anti-inflammatory activity. Table ll below shows the activity of two compounds of this invention (II and Ill) and, for comparison, the known anti-inflammatory agent 6a-fluoro-l 13,2 ldihydroxy- 1G1 -methyl- 1 ,4-pregnadiene-3,20-dione (I), in this test. This activity of the compounds of this invention was most surprising, since the compounds of this invention lack a free or esterified hydroxy group in the 1 1- and 2 l-positions. Moreover, such a group in the 17a -position is unnecessary for the maintenance of activity.

The vasoconstriction test utilized to show clinically the high activity of the compounds of this invention as topical anti-inflammatory agents was conducted as fol lows: On the backs of male patients (18-38 years), the stratum comeum was divided by the application and tearing off of an adhesive film having a width of 2 cm., which application was conducted 20 times at the same spot. As a result, a pronounced hyperemia was thus produced. Then, within the stripped area, under the same application of pressure, approximately 50 mg. of a water/oil salve base containing, in each case, respectively 0.1 percent or 0.01 percent of the compound being evaluated for activity are applied to marked 4 cm areas. The backs of the patients were then photographedat specific intervals with color film (Kodak). In order to evaluate hyperemia and vasoconstriction, the color of the individual zones of the skin on the Kodak color film were translated into brightness values. This was done by projecting sections of the color film through a perforated screen on an interference filter. Such sections difler from one another in brightness depending on the degree of vasoconstriction obtained at that section. As the brightness indicator, a secondary electron multiplier was employed, and for determining the chromaticity value, the anode current of the secondary electron signal was measured. To determine the vasoconstn'ction effect, which is a representative syndrome of topical anti-inflammatory effectiveness, there was measured onset of effect, degree of effectiveness, and duration of effect. The chromaticity value of the treated and untreated stripped skin was determined and compared with the chromaticity value of the normal skin, the chromaticity value of the normal skin being assigned the value 100 and the chromaticity value of the untreated stripped skin was assigned the value 0. Slight, medium, and high vasoconstriction effects were evaluated between and 100.

TABLE II Dos age observation time in hours No. Compound in% l 2 3 4 5 6 I Qrfluoro-llfill-di- 0.1 5 35 65 100 hydroxy-l6 -methyl-L4- 0.01 0 40 50 100 pregnadiene-3-20-dione ll u,llfi-Difluoro-9, 0.1 15 50 85 100 2l,2l-trichloro-l6 0.01 I5 55 85 100 methyl 1 ,4-pregnadiene-3,20-dione Ill 6u,llB-Difluoro-2,9, 0.1 I0 35 80 I00 2l,2ltetrachloro-lfi1 0.01 5 15 60 90 100 methyl- 1 ,4-pregnadiene- 3,20-dione The experimental results represented in Table I] show that with the compounds of this invention, in addition to attaining an earlier onset of efiectiveness, the desired maximum of effectiveness is likewise reached more quickly than in the case of the comparison compound. Moreover, the intensity of effectiveness of the novel compounds is higher throughout during the period of effect than in the case of the comparison compound. Moreover, the side effects caused under the influence of the compounds of this invention are desirably minor.

The novel compounds of this invention are useful for the treatment of a variety of inflammatory conditions, e.g.,

a. topical administration: variety of types of eczemas, neurodermitis, erythroderrnia, first-degree burns, pruritus vulvae and ani, rosacea, erythematodes cutaneus, psoriasis, lichen ruber planus, verrucosus and contact dermatitis; I

oral administration: acute and chronic polyarthritis, neurodermitis, bronchial asthma, hay fever, and others.

The compounds can be employed in the treatment of inflammatory conditions formulated in conventional pharmaceutically acceptable carriers in the forms customarily employed in pharmaceuticals. For oral administration, especially suitable are tablets, dragees, capsules, pills, suspensions and solutions. Suitable excipients for tablets are, for example, lactose, amylose, talc, gelatin, magnesium stearate, and the like.

For topical administration, suitable are powders, solutions, suspensions, aerosols, and vaginal suppositories. For parenteral application, aqueous and oily solutions or suspensions can be employed.

The compounds of this invention are formulated so as to provide, for example l-150 mg. of the effective agent in admixture with 20 mg. to 5 g. of a pharmacologically indifferent excipient, i.e., a pharmace utically acceptable carrier, per unit dosage, e.g., per tablet.

The novel effective agents are usually administered topically at concentrations in the pharmaceutical carrier of between 0,02 and 0,5 percent, preferably 0,05 to 0,2 percent.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

The unknown A "-2.2l-dichloro steroid employed as starting product according to example 3 can be produced as follows:

a. A solution of 25.0 g. of 6 -fluoro-l lB-hydroxy-Z 1- acetoxyl 61 -methyl- 1 .4-pregnadiene-3 .20-dione in 125 ml of tetrahydrofuran and 250 ml of methylene chloride is mixed at -l0 C with 50 g. N-chlorosuccinimide and 62,5 ml of dioxan satured with hydrochloric acid. After 10 minutes the batch is poured into water, extracted with methylene chloride, and the extract is washed with a sodium sulfite-, a sodium hydrogen carbonate solution and with water. After evaporation of the solvent the crude product is chromatographed on silica gel with 1.3 1.9 percent acetone-methylene chloride to furnish 5,95 g. 61 -fluoro-la,2,B-dichloro-l l B-hydroxy-Z l-acetoxyl 6a-methyl-4-pregnene-3 .20- dione, m.p. 177 178 C (from acetone-hexane) 1 120 (chloroform).

UV: e 13 100 (methanol).

b. A mixture of 5.9 g. of 61-fluoro-la,2B-dichlorol 1,8-hydroxy-2 l-acetoxyl 6a-methyl-4-pregnadiene- 3.20-dione, 29.5 ml of dimethylformamide, 5.9 g. of pyridine and 2.95 ml of methane sulfonic acid chloride is heated for minutes under nitrogen, allowed to cool and poured into water. The isolated precipitate is chromatographed on silica gel. After elution with 2.2 3.6 percent acetone-methylene chloride 3.43 g. of 6 fluoro-2-chloro-2 l -acetoxy- 161 -methyl- 1 .4.9( l l pregnatriene-3.20-dione is obtained, m.p. 161 162 C (from acetone-hexane);

[a 16 (chloroform). UV: e =16 000 (methanol).

0. A solution of 23.5 g. of (u-fluoro-Z-chloro-Zlacetoxy- 1 6a -methyl- 1 .4.9( l l )-pregnatriene-3 .20- dione in 235 ml of methylene chloride is mixed with 235 ml of a 0.2 N potassium hydroxide solution in methanol. After stirring for 15 minutes at room temstirred for 30 minutes at C and poured into ice-waterthe precipitate dissolved in methylene chloride. The crude product is chromatographed. After elution with 15 17 percent acetone-pentane 1.56 g. of Q-fluoro-2 -chloro-21-mesyloxy-1Q -methyl-1.4.9( 1 1 pregnatriene-3.20-dione is obtained, m.p. 197 199 C (from acetone-hexane). [a 1,, 8 UV: 2 600.

e. A solution of 6.0 g. of Q -fluoro-2-chloro-2lmesyloxy- 1 Q -methyl-1.4.9( 1 1 )-pregnatriene-3.20-

dione in 90 ml of dimethylformamide is mixed with 12 g. of iithiumchloride and stirred for 16 hours at 100 C, the product is precipitated by pouring into water and isolated by extraction with methylene chloride. The

crude product is chromatographed. After elution with 7.4 10 percent acetonepentane 2.34 g. of Q -fluoro- 2.21-dichloro-1Q -methyl- 1.4.9( 1 l )-pregnatriene- 3.20-dione is obtained, m.p. 185 187 C (from acetone-hexane).

The starting products according to example 1 and 2 can be produced from lQ-methyl-Q -fluoro-4-pregnene- 1113,2l-diol-3.20-dione-21-acetate (obtained from 21- OH esterification with acetic anhydride/pyridine), according to example 4 from prednisolon-2l-acetate and according to example 5 from Q-rnethyl-prednisolon- Zl-acetate.

In all cases the introduction of the 9.1 l-double bond and the substitution of the 21-hydroxyl group by a chloro atom are produced analogous to the methods as mentioned above (c to e).

EXAMPLE 1 At 50C., 5 ml. of anhydrous hydrogen fluoride is mixed with 7.5 ml. of tetrahydrofuranand ml. of methylene chloride. In this mixture, 5.0 g. of Q-fluoro- 2 1 -ch1oro- I Q -methy1-4,9( 1 1 )pregnadiene-3-,20- dione, as well as 5.0 g. of N-chlorosuccinimide are dissolved, and the reaction mixture is allowed to stand for 24 hours at about 0C. Then, the mixture is poured into ice water containingsodium bicarbonate and sodium sulfite dissolved therein. The thus-precipitated s'ubstance is filtered off, dissolved in methylene chloride,

the solution washed with water, dried over sodium sulfate, and evaporated under a vacuum. The residue is chromatographed on silica gel. After elution with 6.8 8.2 percent of acetone/pentane, 1.33 g. of QJIB- difluoro-9,21,21-trichloro-lQ-methyl-4-pregnene- 3,20-dione is obtained, m.p. 204'-205C.' (from acetone/hexane). UV: e 16,400 (methanol); [01925 154 (chloroform).

is converted to 8 EXAMPLE 2 pregnatriene-3,20-dione is reacted, as described in Example l, with hydrogen fluoride and N-chlorosuccinimide. The crude product is chromatographed on silica gel. After elution with 8.5 11 percent acetone/pentane, 1.52 g. of Q ,11B-difluoro-9,21,21-tri-chloro-1Q -methyl-l,4-pregnadiene-3,20-dione is obtained, m.p. 224226C. (from acetone/hexane); [011 +1 23 (chloroform); UV: e 15,700 (methanol).

EXAMPLE 3 EXAMPLE4 4.0 g. of 2l-chloro-17-hydroxy-1,4,9(11)- pregnatriene 3,20-dione are reacted, as described in Example 1, with hydrogen fluoride and N-chlorosuccinimide. The crude product is chromatographed on silica gel. After elution with 4.5 5.5 percent acetone/methylene chloride, 1.18 g. of llB-fluoro- 9,2 l ,Zl-trichloro- 1 7a -hydroxy-l ,4-pregnadiene 3,20-

dione is obtained, m.p. 235236C. (from acetone/hexane). [a 1,, =+136 (chloroform); UV e 15,300 (methanol),

EXAMPLE 5 Following the procedure of example 1 21 chl0ro-17- hydroxy-t'u -methyl-1 ,4,9( 1 l )-pregnatriene-3,20-dione 1 1B-flu0ro 9,2l ,21-trichloro-17 hydroxy-Q -methyl-1 ,4-pregnadiene-3,20-dione.

EXAMPLE6 One g. 1lfl fluoro-9,21,2l-u'ichloro-l7a-hydroxy-6 a-methyl-l,4-pregnadiene-3,20-dione is esterified with 5 ml acetic anhydride and 0,1 g. p-toluolsulfonic acid. After 5 hours at room temperature is obtained 880mg. of v 1 lB-fluoro-9,2l,21-trichloro-17 -acetoxy-Q- methyl- 1 ,4-pregnadiene-3,20-dione.

The preceding examples can be repeated with similar succes by substituting the generically and specifically described reactants and/or operating conditions of this invention for those used in the preceding examples. From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. I

9 l WHATIS CLAIMEDIS: 9. A compound of claim 5, l1/3fluoro-9,2l,2l- 1 A 21 ,21-dichloropregnane of the formula trichloro-17 -hydroxy-1,4-pregnadiene-3,20-dione.

(Hob 10. Process for the preparation of a 21,21-

dichloropregnane of claim 1 which comprises reacting a steroid of the formula 4 I llz(3l R, 3:0 V -1u wherein R is a hydrogen or chlorine atom; R is a hydrogen atom, a fluorine atom, or a methyl group; R,

is a hydrogen atom or a methyl group, R is a hydrogen atom or a free or esterified hydroxy group, and C wherein R R R R and C 43 have the values given represen a ng e o o e bond. above, with hydrogen fluoride in the presence of an N- A Compound of Claim 1 wherein 1 is chloro-acylamide or chloroimide and a reaction sol- 3 A compound of claim 1 wherein R is Cl. t,

A Compound of Claim 1 wherein 2 is l 1. A process according to claim 9 wherein the reacbl 5 gompound of Claim 1 wherein 1= 2 is a tion is conducted for a period of at least 3 hours.

12. A compound of claim 5, llB-fluoro-9,2l,2l- A compound of dam (11 ,1 B i trichloro-l7-hydroxy-6u-methyl-1,4-pregnadienetrichlorol 61 -methyl-4-pregnene-3 ,20-d1one. 2 5 3 20 diOne 7. A compound of claim 4, 61,l lB-difluoro-9,2l,2l- A compound of claim 5 11B f| 9 2| 21 mchloro" 1 1 ,4-pfegnadiene-3 trichlorol 7-acetoxy-(u -methyl- 1 ,4-pregnadiene-3 20- 8. A compound of claim 4, (11,1 IB-dtfluorodione 2 ,9,2 l ,2 l -tetrachloro- 1 (u -methyl 1 ,4-pregnadiene- 3,20-dione. 

2. A compound of claim 1 wherein R1 is H.
 3. A compound of claim 1 wherein R1 is Cl.
 4. A compound of claim 1 wherein R2 is F.
 5. A compound of claim 1 wherein C1-C2 is a double bond.
 6. A compound of claim 4, 6 Alpha ,11 Beta -difluoro-9,21,21-trichloro-16 Alpha -methyl-4-pregnene-3,20-dione.
 7. A compound of claim 4, 6 Alpha ,11 Beta -difluoro-9,21,21-trichloro-16 Alpha -methyl-1,4-pregnadiene-3,20-dione.
 8. A compound of claim 4, 6 Alpha ,11 Beta -difluoro-2,9,21,21-tetrachloro-16 Alpha -methyl-1,4-pregnadiene-3,20-dione.
 9. A compound of claim 5, 11 Beta -fluoro-9,21,21-trichloro-17 Alpha -hydroxy-1,4-pregnadiene-3,20-dione.
 10. Process for the preparation of a 21,21-dichloropregnane of claim 1 which comprises reacting a steroid of the formula
 11. A process according to claim 9 wherein the reaction is conducted for a period of at least 3 hours.
 12. A compound of claim 5, 11 Beta -fluoro-9,21,21-trichloro-17-hydroxy-6 Alpha -methyl-1,4-pregnadiene-3,20-dione.
 13. A compound of claim 5, 11 Beta -fluoro-9,21,21-trichloro-17-acetoxy-6 Alpha -methyl-1,4-pregnadiene-3,20-dione. 